Synapses and axons are targets of inflammation-induced neurodegeneration. Synaptic dysfunction and loss usually precedes degeneration of the neurons, and are early features of several neurodegenerative diseases including Lewy body disease dementia. Our preliminary data show that the complement system is activated after elevation of brain glycosphingolipids, which are involved in the pathophysiology of Lewy body dementia and related disorders. The in vivo experiments outlined in this proposal determine complement activation, the immune system and synaptic neurodegeneration in dementia of the Lewy body type. In addition, in these preclinical animal models, the cognitive effects of inhibiting the complement pathway will be determined. We specifically hypothesize that (1) C1q and the complement pathway is involved in synaptic dysfunction and loss in experimental Lewy body dementia models in which synaptic degeneration and inflammatory response are key pre-degenerative features, and (2) novel stabilized, long-acting antisense oligonucleotides can effectively reduce C1qA and C3 in experimental Lewy body dementia models. These experiments will address whether C1q and C3 are involved in the degeneration of cortical and hippocampal neurons using (a) global brain human Thy1 ?-synuclein overexpression, (b) regional AAV human ?-synuclein expression, and (c) systemic and brain glycosphingolipid-induced ?-synucleinopathy and inflammation using GbaD409V knockin mice. Cognitive behavioral assays include novel object recognition tasks and Y-maze. By peripheral and central knockout in experimental Lewy body dementia models these experiments are also designed to distinguish between the local role of C1q and C3 in eliminating synapses in the brain (by brain antisense oligonucleotide targeting) and the potentially needed phagocytic function and systemic influence (by transgenic knockout). Investigating synaptic loss mediated by modulators of the complement pathway is a paradigm for understanding cortical and hippocampal neuron degeneration in models of Lewy body and related dementias. The findings will impact the understanding and therapeutic options to potentially control complement-mediated elimination of synapses and degeneration of neurons in Lewy body dementia.